Benzenesulphonhydroxamide derivatives and process of producing them



Patented Oc 1937 A w UNITED STATES PATENT orrics BENZENESULPHONHYDROXAM'IDE DERIVA- TIVES AND PROCESS OF PRODUCING Morris S. Kharascli and Otto ltcinmutli, Chicago, 11L, assignors to Eli H11! and Company, Indianapolis, Ind., a corporation of Indiana No Drawing. Application January 28, 1037, Serial No. 121,978

6 Claims. (CL 260-124) Our invention relates to the new product sodium carbonate. The following equation indie l n nes phonhydroxamide, its salts. cates the course of the reaction. and its new intermediate p-acetamidohenzenesulphonhydroxamide; and to the process of producing'them. o 5' Our new final product, p-aminobenzcnesul- (a) P; phonhydroxamide, has been found efficacious, both on oral and on parenteral administration, for the treatment of streptococcic and other in- +HN0H-Ho1+mc0l V 10 fections, especially those of great virulence. Ef- 10 fective oral dosages in adult human cases are of the order of 100-1000 mg., and effective par'enogmm oooo teral dosages of the order of 50-500 mg. I I

The new p-aminobenzenesulphonhydroxamide has the following formula: (p-acetamidobonunt- 1 snlphonyl chloride) I 0 I n-N-a -om lI-N-H 20 0) v -+zmo1+mo+oo.

a d o- -n-on o5 ,o=- NOH WM nlphonliydronnldo) v 30 The p-acetamidobenrenesulphonhydroxamide is It is a pale-cream-colored, almost white, crystalobtained as a solid, and may be separaied in any line solid. It is moderately soluble in cold water, suitable way, as by filtration. This intermedivery soluble in hot water. It is rather more soluate is a new compound in itself. Itmelts with ble in alcohol, ethylene glycol, and propylene decompositionat 190-191 C.,.(uncorr ected). It 35 glycol, either hot or cold, than in'water. It is issoluble in alcohol din alcohol. difquite insoluble in ether and in benzene. It sinflcultly soluble in water. It may be cry ters at 152 C., and melts with decomposition from water-alcohol mixtures (50%). when heated to 156l65 C. (uncorrected). Step 2.-We now boil a of this When heated in water solution for a long period intermediatem-acetamidobenzenssulpbcnhydroxof time it slowly decomposes, especially in neuamide, with a'dilute nonxidizinz mineral acid. tral or alkaline solution. It is more stable topreferably 6N hydrochloric acid, until it is comwnrd heat in water solution on the acid side. P y d s d and considerable To prepare this new product, we proceed as period longer, as for about 30 to minuteato 45 follows: ensure complete hydrolysis. The reaction mix- 45 step 1.- To a water suspension of p-acetamiture is cooled, and the acid is neutralisedin suitdobenzenesulphonyl chloride, we add a water soable manne as with or bilution of slightly more than a molecular equivae carbonate. A solid sepamteaand is suitably coilent of a hydroxylamine salt, suitably the hydrolected, as on a filter. This solid is the desired new ch oride, and make the solution alkaline, as with final product, p-aminob nn'enesnlphonylhymxso This final hydroxamide, may be suitably purified, as by crystallization from water.

An example of our process is as follows:

Step 1.Thirty (30) gms. of p-acetamidobenzenesulphonyl chloride is suspended in 100 cc. of

water, and a solution of ms. of hydroxylamine hydrochloride in 100 cc. of water is added to it. To this we slowly add 28 gins. of sodium carbonate, and mix thoroughly. We allow the whole to stand awhile, say from one-half hour to three hours, within which time the reaction is complete. The reaction product, p-acetamidobenzenesulphonhydroxamide, is collected on a filter, and washed well with cold water, until the washings give no alkaline reaction with litmus. We crystallize this intermediate product from alcohol, from which solvent it separates, on cooling, as white, glittering, needle-like crystals, melting with decomposition at 190191 0. (uncorrected). The yield is almost quantitative.

Step 2.Five (5) gm. of this intermediate, p-aoetamidobenzenesulptmnhydroxamide, is suspended in 30 cc. of 6N hydrochloric acid. The whole is boiled, under a reflux condenser, until a clear solution is obtained; and the boiling is continued for from 30 to 45 minutes longer. The solution is cooled, and neutralized with sodium carbonate. A solid separates, and is collected on a filter and crystallized from water. The yield is good. This solid is the desired final product, p-aminobenzenesulphontwdroxamide.

This final product is effective, on either oral or parenteral on, to combat streptococcic and other infections. It may be administered orally in tablet form, or in suspension or solution in any non-toxic menstruum. It may be administered subcutaneously, intramuscularly, or intravenously in any suitable non-toxic solvent; for which we find the glycols, especially propylene glycol, mixed with water if desired, very advantageous. It may also be administered,

product, p-aminobenzenesulphoneither orally or subcutaneously or intramuscularly, in the form of the'salt of a non-toxic acid having a strength not less than that corresponding to an ionization constant of 10- such as the hydrochloride, sulfate, lactate, tartrate, maleate, fumarate, succinate, etc.-which salts may be formed by treating the p-aminobenzenesulphon hydroxamide with the proper acid; the salt being dissolved in a suitable solvent, most conveniently water, for subcutaneous or intramuscular administration. The general formula for these salts is:

with X representing the negative ion of such an acid as just defined.

We claim as our invention: 1. The new product the following formula:

in which R represents a radical of the class consisting of the NH'! (amino) group, the

(acetamido) group, and -NH3-X group with X representing the negative ion of a non-toxic acid having a strength not less than that corresponding to an ionization constant of 10- 2. The new product p-aminobenzenesulphonhydroxamide, which is represented by the following formula:

3. The new product p-acetamidobenzenesulphonhydroxamide, which is represented by the following formula:

4. The process of making p-aminobenzenesulphonhydroxamide, which consists in treating pwhich is represented by acetamidobenzenesulphonyl chloride with a, hymetnmidobenle emlphonhydronmide with a didroxylamine salt and making alkaline, to yield lute non-oxidizinc mineral acid. andneumlillnl. p-acetamidobenmenemflphonhydrmmide as an 6. The process of making p-wetamidohemeneintermediste, and boiling that iiitermediate with siflphonhydroxamide. which consists in treatinz pizing, to yield desired p-eulldroxylamine aaltmnd making alkgiine.

sm mrmmnzp-mnomnmnmmu'sa.

esulphonyl chloride with a hy- 5 

